Download Rationale For and Results to Date from Proton Beam

Rationale For and Results to Date from
Proton Beam Radiation Therapy
Herman Suit
Abstract
planning and dose delivery should be identical.
The rationale for use of proton radiation therapy
is that by proton beams a superior dose
distribution feasible is readily achieved for nearly
all anatomic sites. This is based of the law of
physics that the range of a proton in a material
is finite. Hence, beams can be designed that
have a uniform dose across the target and
virtually zero dose deep to the target and a
modestly lower dose proximal to the target
relative to that of a high energy x-ray beam.
Published results by proton therapy have been
obtained that are judged superior to those for
x-ray therapy for uveal melanoma,
chondrosarcoma and chordoma of the skull
base, chordoma of sacrum, squamous cell
carcinoma and adenocystic carcinoma of the
H/N region and hepatocellular carcinoma.
C ion therapy provides similar biologically
effective dose distributions to those by proton
beams. There is, however, a modest dose
distribution advantage for 12C ion beams in their
more narrow penumbra or dose fall-off at the
lateral edge of the beam. Of serious interest is
the potential of a clinical gain due to the high
LET of 12C ion beams. Results that have been
published for 12C ion therapy appear to yield
higher tumor control rates for chordoma of the
skull base, mucosal melanoma of the H/N, renal
cell carcinoma and early stage prostate
carcinoma.
12
My opinion is that there is no valid rationale for
Phase III clinical trials of two low LET beams one
of which delivers fewer doses to normal tissues.
This refers to trials of x-ray vs proton beams for
sites for which comparative treatment plans
demonstrate superior dose distribution for
proton beams. In contrast, there is a clear and
strong rationale for Phase III trials of protons vs
12
C ions with only one variable, LET. The
fractionation and all technical aspect of treatment
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Why Proton Beams in Radiation Therapy?
The single basis for protons rather than x-rays
in radiation therapy is quite simple, ie a superior
dose distribution. That is, for most tumor
anatomic situations there is a lesser radiation
dose to normal tissues for a defined dose and
dose distribution to the target volume than is
achievable by the most technologically
advanced technique with x-ray beams. The yield
is an increased tolerance by the patient of
radiation dose and hence higher doses may be
administered. The result is a higher tumor control
probability [TCP]. A therapeutic gain is a higher
TCP for a specified NTCP. Were the TCP judged
acceptable, eg ³0.9, an alternate strategy could
be to maximize the reduction of NTCP at an
accepted TCP. Thus, there would be a definite
clinical gain for either approach.
The superior dose distribution of a proton
treatment plan is the result of a law of physics
that the range of a proton beam in tissues is
finite1 . That range is a function of the beam’s
initial energy and the density of the matter in the
beam path. A pristine proton beam penetrates
a defined material a distance determined by the
entrance beam energy and the material density.
The penetration depth is highly uniform. For
example a beam with a range of 200 mm in pure
water, the variation in range of the individual
protons is only a few mm [Michael Goitein,
personnel communication, 2010]. Thus, a well
designed distribution of proton energies yields
a uniform dose across the volume of interest,
the Spread Out Bragg Peak or SOBP and
virtually zero dose deep to the SOBP. This is
shown in Fig. 1a. The sharp contrast between
the depth dose curves of high energy x-ray
beams and a clinical proton beam is illustrated
in Fig.1b. The red areas indicates the volumes
that are irradiated but that are not suspected of
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involvement by tumor, ie negative or not wanted
dose. For very superficial tissues, there would
be a thin depth that would receive a higher dose
by the proton than by x-ray beams, indicated by
the green area. This is due to dose build-up over
the superficial 5-10 mm of tissue by high energy
x-ray beams. For tumors close to the surface, a
small portion of the total dose is given by x-ray
beams of appropriate energy to reduce surface
dose. For all but a small fraction of tumors,
B
treatment is by multiple fields so that dose to
superficial tissues is not a major consideration.
Fig.1. a. Depth dose curves of a series proton
beams of well selected distribution of energies
are at the bottom of the figure. The yield is the
uniform dose across the depth of interest, the
SOBP at the upper part of the figure. b. Depth
dose curves of a clinical proton beam and a high
energy x-ray beam demonstrating the superior
dose distribution of the proton beam.
Fig 1.
a Depth dose curves of proton beams of well selected energies to produce the uniform dose across the depth of concern, viz
the SOBP. b. Comparison of depth dose curves of a clinical proton beam and a high energy x-ray beam.
A critical point in comparing the two beams is
that there is similar flexibility in delivery of proton
and x-ray dose. That is, there can be the same
number of beams, direction of beams, co-planar
or non co-planar, intensity modulated. A recent
and elegant technology that can be employed
equally by protons and x rays is [4D image
guided radiation dose delivery [4D IGRT] [3].
Advances in the technology of radiation
oncology have been principally those planned
to provide a superior dose distribution. These
include the progressively higher energy x-ray
beams. These firsts are mentioned: 100 kVp at
Jefferson Hospital, Philadelphia in 1907; the 1
MV Van de Graaff machine at the Huntington
Cancer Hospital of Harvard University in 1937;
the 22 MV Betatron at the University of Illinois in
1948 and the 8 MV linear accelerator in 1953 at
Hammersmith hospital, London. [13]. These
have been accompanied by the introduction of
portal imaging, simulators, computer based
treatment planning systems, gantries, greatly
improved patient positioning, imaging [CT, MRI,
PET US and other] and the above mentioned
start of 4 D IGRT. These technical advances have
generated truly major gains in dose distribution
and, hence, clinical outcomes. Our good fortune
is that many more are “coming down the pike”.
One critical advantage of radiation treatment is
that the dose is well localized to the target
volume, ie quite low doses to tissues not close
to the target tissues. This is even more the case
for proton irradiation. The total body integrated
dose by proton radiation therapy is ~ half that
of the high technology x-ray method increasingly
employed today, viz intensity modulated x-ray
therapy, IMXT [22].
An important additional fact is that a superior
dose distribution that reduces radiation dose to
chemotherapy sensitive normal tissues permits
higher doses of drugs, hence greater anti-tumor
effect.
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NTCP should be assessed from long term followup observations, viz 10-25 years because of the
fact that late injures are late. This is also valid for
assessing toxicity of chemotherapeutic agents.
A book on the status and potential of proton
radiation therapy by DeLaney and Kooy [7] has
been published, reflecting the widening interest
in this technology.
Biological Effectiveness of Clinical Proton
Beams Relative to High Energy X-Ray Beams.
This question has been examined is detail using
in vitro and in vivo systems. J Robertson of the
Harvard School of Public Health determined the
RBE for 160 MeV protons for the H4 hepatoma
cell line in vitro at the start of our proton therapy
[28]. Then came the series of in vivoexperiments
by Tepper etal and Urano etal at the MGH/HCL
[37, 40, 41] and a goodly number of other
investigators employing a spectrum of normal
tissues as well as tumors. In 2002, Paganetti etal
reviewed the RBE values from all published in
vivo studies. The result was that the mean RBE
[relative to 60 Co photons] was 1.1, with no evident
dependence of RBE on dose or on tissue
investigated [24]. This value was approximately
equivalent to that of 250 kVp x-rays. Accordingly,
a proton dose of 70 Gy would be biologically
the equivalent of 70 x 1.1 or 77 Gy by a high
energy x-ray beam. This RBE value for clinical
proton beams has been has been adopted by
the International Commission on Radiological
Units [26]. The result has been a much simplified
treatment planning. That is, no concern as to
Fig 2a.
the dependence of RBE on dose per fraction,
tissue or other factors as is the situation for 12C
ion therapy.
Examples of Proton and X-Ray Treatment
Plans for Several Anatomic Sites.
Dose distributions are presented in Figs. 2-5 for
4 anatomic sites. The tumor dose has been
planned to be the same for the x-ray and proton
treatments. These are clear in showing lower
dose to normal tissues for comparable tumor
doses.
Fig.2 demonstrates the dose distribution for
intensity modulated x-ray and proton therapy to
a chondrosarcoma of the superior pubic ramus.
The intensity modulated treatment method is a
comparatively new and very high technology
treatment method. Fig. 3. shows the dose
distribution for treatment of a patient with a skull
base tumor, by intensity modulated protons and
x rays. Figs. 4 and 5 present treatment plans for
elective irradiation pelvic lymph nodes and for a
retrobulbar sarcoma. I know that you have seen
other examples of proton dose distribution in
treatment plans for the pediatric patients in
presentations of the excellent work of Tarbell,
Yock and associates at earlier SIOP meetings.
Mention is made here of a few of their
publications on this subject. [36, 44, 45]
Figs 2 and 3. Dose distribution for proton and
x-ray treatment, using intensity modulated
delivery techniques, for a chondrosarcoma of
the superior public ramus and a skull base tumor.
Fig 2b.
a. and b. Dose distribution of an intensity modulated x ray and a proton treatment plan for a chondrosarcoma of the public
ramus.
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SECTION
Fig 3a.
B
Fig 3b.
a. and b. Dose distribution of an intensity modulated x ray and a proton treatment plan for a tumor of the skull base.
Fig 4a.
Fig 4b.
a. and b. Dose distribution of a proton treatment plan for a elective irradiation of the pelvic lymph nodes. b. A proton treatment
plan of a retrobulbar tumor in a pediatric patient
Fig 5a.
Fig 5b.
a. Beam contour device for one field of proton treatment of a patient. b. The plastic devise made for each field of each patient
to provide the planned penetration of the proton beam in each voxel of tissue in the patient.
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Figs. 4 and 5. Proton treatment plans for elective
irradiation of pelvic nodes and for a retrobulbar
tumor.
Clinical Results of Radiation Therapy
The first cancer patient treated by fractionated
dose proton beams with intent to cure
My clinical experience before recruitment to the
MGH in 1970 had been 2 years a the NCI using
the 2 MV Van de Graaff unit. Then for 10 years at
the MDACC, I had regular access to the higher
energy betatron beams. In my judgment and that
of my colleagues was that the higher energy
beams were clinically far superior to the 250 xray beams. Shortly after coming to the MGH, I
was greatly fascinated by the real prospect of
clinical study of proton beams for treatment of
cancer patients using the Harvard Cyclotron
Laboratory [HCL]. Since 1961, there had been
an ongoing program of single dose proton
irradiation of intra-cranial lesions by the
neurosurgical group of R Kjellberg and W Sweet
using stereotactic radiosurgery [SRS].
Our proposal in 1971 to use the cyclotron 4 full
days per week for proton radiation treatment of
cancer patients with the intent to cure was
accepted with open enthusiasm by the HCL
team. I did not know at the time that the Harvard
Physics Department had been planning to close
the facility due to the low utilization and high cost.
Were our program to be funded, it would be a
significant factor in a continued active HCL. Our
excellent fortune was to receive NCI grants for
the support of this program in 1975. This has
continued and recently has developed into a joint
program with the proton center at M D Anderson
Cancer Center.
Planning commenced in 1971 to prepare for our
program. There was impressive talent at the HCL
in the persons of A Koehler, Bill Preston and
Richard Wilson. In 1972 Koehler and Preston
published a paper on the comparative dose
distribution of protons, x-ray and electrons [20].
I had the extremely great fortune of recruiting
an exceptional young nuclear physicist from UC
Berkeley very early in 1972. He had decided to
use his talents in medicine. This was Michael
Goitein, a graduate of Oxford University and his
Ph D from Harvard 2 . There was initiated a
complex series of projects in dose
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measurements, construction of the patient
support system, method for treatment planning
and modifying the room in order to treat all body
sites.
The proposed strategy was to generate long
term survival outcome data relative to that
obtained by x-ray treatment. The plan was to
have a single variable, namely dose distribution.
That is, the dose fractionation would be the same
as employed in conventional high energy x-ray
therapy, viz ~ 2 Gy(RBE)3 .
Treatment of our first patient commenced in Dec
1973 on a 4 year old boy with a large posterior
pelvic rhabdomyosarcoma and no detectable
metastatic disease. To our knowledge, he was
the world’s first patient treated by proton beams
at standard dose levels per fraction and with the
intent to cure. This patient, in treatment position,
is shown in Fig. 6a. Bi-planar radiographs were
taken to determine to the position of the target
viz a viz the beam. This procedure was repeated
until the target was aligned on the beam with
high accuracy. Treatment was a combination of
HCL protons and betatron x rays of the Boston
Medical Center. I had worked with high energy
x-rays of a betatron at the MDACC and wanted
the same for MGH patients. This was achieved
by leasing the betatron for each afternoon. This
arrangement continued until our new center was
opened in 1975 with an array of linear
accelerators. Additionally, the patient had
chemotherapy; the effectiveness in 1974 was
modest for this category of tumors. There was
complete regression and no GI symptoms as
there has been only a very low dose to the GI
tissues. Regrettably he developed fatal multiple
metastatic lesions. Of perhaps interest to this
meeting is the fact that the last patient treatment
at the HCL was also a child. We closed the HCL
and transferred to our new proton therapy center
at the MGH in 2001, the Francis H Burr Proton
therapy Center.
Due to the high TCP for a very large fraction of
pediatric carcinomas and sarcomas by the
present multi-disciplinary management strategy,
the practice is not to raise dose to the evident
tumor but to concentrate on techniques to lower
doses to normal tissues, viz decrease the
frequency and severity of late treatment related
morbidity. This is the principal interest in proton
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therapy for pediatric patients.
Here, selected results of proton treatment of a
larger experience with tumors in adult patients
are considered.
Skull base chondrosarcoma. Rosenberg et al
reported on the MGH series of 200 patients
treated by a combination of protons and x rays
to a dose of ~72 Gy(RBE) 4 with a 10 year local
control rate of 98% [29].
Skull base chordoma. Ares et al. have reported
a local control rate at 5 years of 81% following
74 Gy(RBE) in the Paul Scherer Institute, near
Zurich. They employed the newer proton beam
technique of actively scanning of small beams
[1]. This permits the higher target dose. At the
MGH, we utilize passive scanned beams and
delivered 69 Gy(RBE) with the lower 5 year local
control rate of 59% as reported by Terahara et al
[38]. Dose level is the determinant of TCP of
tumors of a specified type, grade and volume.
Sacral chordoma. Delaney et al [8] reported
that 8 of 9 patients treated by proton radiation
alone, ie no surgery, for sacral chordoma to 74
Gy(RBE) and had an actuarial 5 year local control
of 87%. The one local failure was in a patient
treated for a post surgical resection recurrent
chordoma.
Fig 6a.
B
Uveal melanoma. This was a collaborative
program between the HCL, the Massachusetts
Eye and Ear Infirmary [MEEI] and our team at
the MGH. In 1975 we commenced proton
treatment of uveal melanoma5 . The lesions are
small, usually less that 1 cm, and the expectation
was that very high doses could be delivered
safely and provide a high TCP, despite the
general opinion at the time that malignant
melanomas were extremely resistant. The first
patient to receive proton treatment of a uveal
melanoma is shown in the treatment position in
Fig.7. We started at 10 Gy(RBE) x 5 or 50
Gy(RBE) in 5 days. Shortly, as tolerance
appeared to be very high, dose was increased
to 14 Gy(RBE) x 5 or 70 Gy(RBE). Results have
been good, viz local control of 95% at 15 years
for the series of 2069 patients as reported by
Gragoudas et al. [18, 19]. Similar results have
been obtained from centers in many countries.
For example, Eggers et al in references 10
and11. reported from Switzerland on a series of
2435 patients with local control of 95% at 10
years. The enucleation rate in proton treated
patients has been 3-8% [35]. The one report for
stereotactic photon treatment using the same
dose to the tumor and, hence, the same TCP at
2.9 years, but the enucleation rate was 13% [9].
Fig 6b.
a.The first patient treated by low dose per fraction with the intent to cure. This patient was a 4 year old boy with a posterior
sarcoma of the pelvis. b. The first patient to be treated by proton beams for a uveal melanoma.
Adenocystic carcinoma of the Head and
Neck. In a series of 23 patients with locally
advanced adenocystic carcinoma treated to 76
Gy(RBE) at the MGH–HCL by protons, the 3 year
local control result was 93%, as described by
Pommier et al [25].
Squamous cell carcinoma of the Head and
Neck. For 29 patients with locally advance
squamous cell carcinoma patients were treated
to 76 Gy(RBE) at Loma Linda proton center, local
control at 5 years was 88% as reported by Slater
et al [32].
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Hepatocellular Carcinoma. From Tsukuba,
Japan, the local control at 5 years in their series
of 162 patients with hepatocellular carcinoma
was reported by Chiba et al. to be 87% [4].
Mornex et al. in France had local control in 19 of
25 patients at 2.4 years after x-ray treatment and
4 patients developed GIII toxicity [23]. This
compares with 5 patients among 162 patients
at Tsukuba that developed =GII injury after
proton therapy and longer follow-up observations
Prostate carcinoma. Results of two phase III
proton therapy trials have demonstrated that
TCP does increase with dose, no surprise.
Shipley et al. [31] conducted a Phase III trial of
proton therapy on 189 patients with T3-4, N0-2,
M0 stage disease and clinical local control as
the end-point. Local control rates were 81% and
92% at 5 years at dose levels of 67.2 and 75.6
Gy(RBE), respectively. Treatment was 50.4 Gy
pelvic dose by x rays and then a proton boost to
67.2 or 75.6 Gy(RBE). Treatment was radiation
alone, viz no hormonal therapy.
Results of a Phase III trial have been reported
by reported by Zietman et al that was conducted
by MGH and Loma Linda for stages T1b-2b
prostate cancer. Doses were 70.2 and 79.2
Gy(RBE) to 197 and 196 patients. The 5 year
biochemical control rates were 61% and 80%,
respectively. [46]. The treatments were 19.8 or
28.8 Gy(RBE) proton boost dose and then 50.4
Gy by x rays to larger pelvic fields to the pelvis.
These patients were treated by radiation alone.
Carbon [ 12C ] Ion beam Therapy
C ions are also positively charged particles but
massive relative to a proton, viz by a factor of
12. The clinical interest in 12C ions is based on
the fact that their tracks are substantially more
densely ionized, ie higher liner transfer of energy
or LET to the irradiated material. This high LET
results in higher biological effectiveness [RBE]
than protons. Three radiobiological features of
the LET of clinical 12C ion beams may be
important for radiation therapy are: 1] a lower
oxygen enhancement ratio, viz lesser impact of
hypoxic regions in tumor tissue on radiation
response; 2] a smaller variation in radiation
sensitivity with position in the cell replication
cycle; and 3] a reduced ability to repair damage
from high LET radiation. As of this date, a clinical
benefit of high LET radiation has not been
12
118
demonstrated. Regarding item 3, the available
data provide no evidence that tumor cells have
an inherently higher sensitivity to high LET
radiations than do normal cells. For item 2, this
appears to be a minor consideration at the LET
values of clinical 12C ion beams. There several
tumors that have demonstrated hypoxic regions,
viz squamous cell carcinoma of H/N region,
uterine cervix, prostate adenocarcinoma among
others. Clinical studies of H/N squamous cell
carcinoma by fast neutron [high LET] and 12C
ion beam therapy have not demonstrated higher
TCP values than by x-ray or photon beams. Suit
et al. have recently reviewed the local control
results of proton and carbon therapy [35].
Meaningful assessment of the efficacy proton
and carbon ion therapy is not feasible at present
as the proton treatments have been largely
based on conventional dose per fraction
schedules while carbon ion therapy has been
hypofractionated, viz large doses per fraction.
The actual local control rates as published
indicate higher rates by 12C ion therapy for
chordoma of the skull base, prostate carcinoma,
mucosal melanoma of the H/N region and
primary renal cell carcinoma. In contrast, proton
therapy results appear to be higher than those
by 12C ion therapy for chondrosarcoma of the
skull base, squamous cell carcinoma and
adenocystic carcinoma of the H/N region. The
results for chordoma of the sacrum, uveal
melanoma and hepatocellular carcinoma are
approximately equivalent. For early stage
NSCLC, the short term local control results are
similar for x rays, protons and 12C ions as the doses
employed are very high for each beam category.
There is an unambiguous need for Phase III trials
of 12C ions vs protons with only a single variable,
LET. That is. the dose fractionation needs to be
identical for both arms. There must also be
standard technology of treatment delivery,
definition of the margin for suspected sub-clinical
extension of tumor scoring of local control
results, viz distinction between local vs marginal
failure and quality of life. At present there is nontrivial variation in these clearly important factors
between the several proton and carbon ion
therapy centers.
Are clinical trials of proton therapy vs x-ray
therapy warranted?
My assessment is that the answer is a clear no,
SECTION
as discussed in some detail earlier [33]. This
opinion is based on the fact that comparative
treatment plan studies can demonstrate the dose
to be delivered to each point in the patient with
narrow confidence limits. That is, the stated
doses to be delivered are the result of physics
and not opinion; they can be and are very
frequently measured. Provided that the
comparative treatment plan demonstrates a
lower dose to normal tissues, a trial for that tumor
category is inappropriate. That is, we have
approximately 100 years experience in the
administration of low LET radiation to human
tissues. That radiation can injury normal tissues
is a fact. There is no known advantage to any
patient to have radiation administered to any
tissue. This pertains for doses down to levels
that can be measured.
There is no rationale known to me for proposing
a long term and costly study to examine if there
is an advantage to administering a lower dose
of a known toxic agent to uninvolved normal
tissues of human patients. Our use of clinical
trials and clearly limited resources should be
directed to study of important questions. One
example would be Phase III trials to determine if
high LET radiation treatment of epithelial and
mesenchymal neoplasms yields superior results,
viz a higher TCP for a defined late effect NTCP.
Another significant question, what should be the
dose and fractionation protocol. Several
analyses of late tissue injury following proton
therapy have been published, two are mentioned
here [6, 30]. Clearly more work in this area is
warranted. Importantly, there is a need to assess
even more than has been performed trials to
evaluate to dose and timing of radiation and
chemotherapy.
A personal experience while at the MDACC that
might be of interest is briefly mentioned. I was
recruited from the NCI in 1959 and within a few
months, Gilbert Fletcher, Chief of the department
called me to his office and stated that it would
be good for me to learn a bit of thinking by some
of our “c ollea gues”. The NCI had calle d a
meeting to discuss the demand by a number of
prominent general radiologists. They were
insisting that the federal government not allow
any additional 60Co units to be installed in the
US until there were clinical studies that
demonstrated a clinical gain relative to 250 kVp
B
x-ray beams. Fletcher stated that he would not
waste his time going to Bethesda and participate
in such a senseless discussion. However, as I
was the youngest faculty in the department I
should attend. He further opined that the
experience would be instructive. The critical fact
is that for 10 x 10cm fields of a 60Co and a 200
kVp [1.5mm Cu HVL] beams the dose to the skin
is 40% for the 60Co radiation vs 99% for the 250
kVp rays. Further the doses at10cm depth are
58% vs 36% of the surface dose respectively.
Additionally the dose to bone in the beam path
is substantially lower for 60Co than the 250 kVp
radiations. These facts made clear the clinically
significant advantages for 60Co irradiation. That
is no concepts were one to accept physically
measured doses. As Fletcher predicted, there
was no perceptible slowing of the installation of
the 60Co units after that NCI meeting nor was
there any action by the NCI.
Historical Notes
Protons. The proton was discovered in 1919 by
E Rutherford at Manchester, England. He did this
by bombarding nitrogen gas with alpha particles
and observing the ejected protons. The
remaining atom had become17 O. This
constituted the first man produced alchemy [34].
Mention is made that Rutherford much earlier
was the first to understand the nature of
radioactivity, ie there is a change from one
element to another or natural alchemy. Further,
he stimulated two of his young faculty, Cockcroft
and Walton [5] at the Cavendish Laboratory at
Cambridge to develop much more energetic
proton accelerators in order to study to
constituents of the atomic nuclei. This was
accomplished in 1932 for the bombardment of
lithium with energetic protons resulting in 2
helium atoms, viz the first artificial alchemy.
Accordingly, Rutherford could claim the title as
the world’s first alchemist.
In 1946, protons and heavier charged particles
were proposed for radiation therapy by Robert
Wilson a young nuclear physicist at Harvard. This
was published in Radiology in 1946 and
discussed the rationale quite fully and
convincingly [42]. Wilson had just returned from
several years of important work on the
Manhattan project at Los Alamos. Although
extremely intelligent and career ambitious6 , he
119
like many physicists at Los Alamos were deeply
concerned that the first military use of the bomb
was against civilian targets. He decided that he
must make an “atonement for involvement in the
development of the bomb at Los Alamos” by
making a contribution from nuclear physics that
would benefit all of humanity [43]. He clearly was
successful as evidence of the very large and
positive impact of that paper.
The first study of the potential of proton therapy
was by C Tobias at UC Berkeley in 1952 [39].
The first report of treatment results was by
Lawrence in 1957 [21] Later carbon, neon and
other heavy ion beams were studied at Berkeley.
This was followed by programs at Uppsala,
Sweden in 1957, at MGH in 1961 at Dubna
in1967 physics research center north of Moscow,
Moscow in 1969 and St Petersburg in 1975 [34].
These programs were almost exclusively single
dose treatment of intracranial lesions, stimulated
by the success of stereotactic radiation surgery
of Leksell and team based on x-ray beams. An
important factor for most of these centers was
the extremely limited beam time for medical
studies.
Protons are of interest also in that there are by a
large margin, the most numerous particle in the
universe. Namely the estimate is that there are
~10 79 protons and a similar number of electrons
[27]. The number of neutrons are estimated to
be 3 x 1087 , or a ratio of ~3:1 protons to neutrons.
Also, perhaps of interest is that the half life of
protons is estimated to be >1032 years, based
on quite extensive experimental studies. Namely
to this date not a singe proton decay has been
observed. The number of photons is larger than
that for proton by a factor of ~ 109 or a total of
some 1088 photons in the universe. For the
human body, hydrogen atoms are on average
estimated to be 63% of the total. The next most
common atoms are oxygen at 25.6%, carbon at
9.5% and nitrogen at 1.3% [2].
Discussion & Conclusions
Proton treatment plans have superior dose
distributions for most anatomic sites relative to
the optimal x-ray treatment plans and
accordingly provide the basis for increasing
dose to the target viz increasing TCP.
Alternatively, the target dose may be kept
constant and attention directed exclusively to
120
decreasing risk of normal tissue injury. Improved
local control results appear to have been
obtained by proton therapy relative to x-ray
therapy of skull base chondrosarcoma and
chordoma, chordoma of sacrum, H/N squamous
cell carcinoma and adenocystic carcinoma and
hepatocellular carcinoma. Additional clinical
results at long term follow-up are needed for
assessing clinical gains for a larger number of
sites studied. With the rapidly increasing number
on proton centers, a much more meaningful
evaluation of clinical results should be available
in 5-10 years. For me, Phase III clinical trials are
not warranted for those sites that demonstrate
a superior dose distribution by proton beams
as both x rays and clinical proton beams are low
LET.
Carbon ion beam therapy is of potential clinical
benefit due to either the high LET and or the
more narrow penumbra. The available data
indicate a gain in local control rate relative to
proton treatment for chordoma of skull base,
prostate carcinoma, renal cell carcinoma and H/
N mucosal malignant melanoma. The results
appear similar for hepatocellular and early stage
NSCLC. There is a need for Phase III trials of
proton vs carbon ion therapy. The design should
feature a single variable, LET. Critical trial design
needs to require identical dose fractionation, all
technical features of the dose delivery and
outcome assessment.
1
This applies similarly to heavier ion beams, eg helium,
lithium and carbon.
2
Goitein was highly creative and productive. Note that he
developed the first computer based treatment planning
system used clinically, the technique for “Beam’s Eye” view,
calculation of uncertainty in the treatment plan and
calculation of the impact of density heterogeneity on proton
dose distribution and others [14-17]
3
Gy(RBE) is the dose in Gy multiplied by the RBE, ie 1.1.
5
E Gragoudas of the MEEI, the HCL and MGH teams.
6
Robert Wilson was appointed to develop the Fermi Lab in
1967. He did this ahead of schedule and below budget
[12]. He led the development of the first accelerator. In
1977, the Fermi team discovered the Bottom Quark. Wilson
laid out the general architectural plans of a truly impressive
central building. Widely rated as a structure of architectural
beauty. One feature was the openness of the office spaces,
viz no closed spaces or solid walls. Additionally he was a
sculptor of significant reputation The initial accelerator was
replaced by the Tevatron in 1983 as the world’s was the
largest and most powerful particle accelerator until the
Large Hadron Collider began operation near Geneva.
SECTION
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